Early Screening for the Parkinson Variant of Multiple System Atrophy: A 6‐Item Score

Abstract Background A 4‐item score based on ≥2 features out of orthostatic hypotension, overactive bladder, urinary retention and postural instability was previously shown to early distinguish the Parkinson‐variant of multiple system atrophy (MSA‐P) from Parkinson's disease (PD) with 78% sensitivity and 86% specificity. Objectives To replicate and improve the 4‐item MSA‐P score. Methods We retrospectively studied 161 patients with early parkinsonism [ie, ≤2 years disease duration or no postural instability, aged 64 (57; 68) years, 44% females] and a diagnosis of clinically established MSA‐P (n = 38) or PD (n = 123) after ≥24 months follow‐up. Results The 4‐item MSA‐P score had a 92% sensitivity and 78% specificity for a final MSA‐P diagnosis. By including dopaminergic responsiveness and postural deformities into a 6‐item score (range: 0–6), reaching ≥3 points at early disease identified MSA‐P patients with 89% sensitivity and 98% specificity. Conclusions The 6‐item MSA‐P score is a cost‐effective tool to pinpoint individuals with early‐stage MSA‐P.

Distinguishing the Parkinson-variant of multiple system atrophy (MSA-P) from Parkinson's disease (PD) is often difficult at early stages due to overlapping clinical features. 1Such suboptimal diagnostic accuracy is a major hurdle for patient's counseling and disease-modifying trials targeting early disease phases. 2 Clinicopathological studies consistently reported that postural instability and autonomic failure emerge earlier in MSA-P than in PD. 3,4 In a recent study by the Innsbruck group, the combination at early disease of two or more clinical features including orthostatic hypotension (OH), symptoms of overactive bladder, urinary retention and postural instability into a 4-item MSA-P score indeed yielded a balanced sensitivity (78%) and specificity (86%) for a final MSA-P diagnosis. 5ditional clinical MSA red flags were also shown to differentiate MSA from PD after an average disease duration of 5 years and may further increase the diagnostic accuracy for MSA-P earlier in the disease course. 6n the present cooperation between the Tel Aviv Neurological Institute, the Belgrade Neurology Clinic, and the Innsbruck Department of Neurology, we aimed at: 1. Replicating the 4-item MSA-P score in an independent cohort of patients with recent onset of parkinsonism; 2. Verifying whether an expanded version of the MSA-P score entailing additional clinical MSA red flags and information on dopaminergic responsiveness increases the clinical diagnostic accuracy for early MSA-P.

Study Population
The medical records of patients with parkinsonism who had undergone a head-up tilt or standing test at the Tel Aviv or Belgrade site between 2009 and 2021 were screened.Patients were retrospectively included, if fulfilling the following criteria:

Clinical-Demographic Data-Set
For each patient, a local study team member extracted the following information from the medical records contemporary to the head-up tilt or standing test: 1. Clinical-demographic characteristics (age, sex, disease duration from the beginning of motor symptoms, age at disease onset, H&Y stage); 2. Medication schedule (number of drugs/day, L-Dopa equivalent daily dose, 9 anti-hypotensive or anti-hypertensive medication intake); 3. Presence of diabetes or other cardiovascular comorbidities (ie, hypertension, ischemic, arrhythmic or structural heart disease); 4. Documented postural instability within 2 years from motor onset 10,11 ; 5. Symptoms of overactive bladder (urinary urge, incontinence or use of appliances), urinary voiding difficulties (based on medical history or post-void residual urine volume >100 mL, 12 whenever available), postural deformities (including Pisa syndrome, disproportionate antecollis, contractures of the hands or feet), 6 bulbar dysfunction (dysphonia, dysarthria or dysphagia), 6 respiratory symptoms (stridor, inspiratory sighs) 6 or emotional incontinence 6 ; 6. Dopaminergic responsiveness, ie, good, poor or undetermined, as defined in the former Innsbruck study. 5

Head-Up Tilt and Standing Test
4][15] OH was defined by a BP fall ≥20/10 mmHg within 3 min in the upright position. 16

Diagnostic Gold Standard
The diagnostic criteria for clinically established MSA 7 and PD 8 were retrospectively applied to the last available visit of each patient by experienced Tel Aviv or Belgrade investigators other than those collecting the clinical-demographic information, and served as a clinical diagnostic gold standard.

Statistical Analysis
Dichotomous variables were summarized by frequency (percentage) and compared with the Χ 2 or Fisher's exact test.Quantitative variables were tested for normality with the Kolmogorov-Smirnov test, reported by median (1st quartile; 3rd quartile) and compared using the Tor Mann-Whitney-U test.
We first compared the pooled Tel Aviv and Belgrade MSA and PD cohorts with the original Innsbruck study population used to generate the 4-item MSA-P score. 5The clinicaldemographic characteristics of the newly recruited MSA versus PD cohorts were subsequently compared in a univariate fashion and the 4-item MSA-P score was calculated for each patient.The diagnostic accuracy of a cumulative score ≥2 at early disease (score range: 0-4) in identifying patients suffering from MSA-P was subsequently weighed against the neurological diagnosis at last available follow-up (sensitivity, specificity, positive and negative predictive value, area under the ROC curve).
In a second step, a decision-tree algorithm for a final MSA-P diagnosis was built with an observer-independent CHAID methodology by adding additional MSA clinical red flags 6 and information on dopaminergic responsiveness to the previously calculated 4-item MSA-P score (fixed first decisional node).The robustness of the model was verified with a cross validation technique.
The additionally identified characteristics, which earlydistinguished MSA-P from PD were used to expand the MSA-P score that was recalculated for each patient.A Youden-index was applied to identify the score cut-off with the highest diagnostic accuracy for a final MSA-P diagnosis.This was again verified towards the final neurological diagnosis.
Statistical analysis was performed with IBM-SPSS and Med Calc.Two-tailed P-values <0.05 were considered statistically significant.A Bonferroni correction was applied to multiple testing.

Study Population
Thirty-eight patients with MSA and 123 with PD were included in the present study.The clinical-demographic characteristics of the study population are summarized in Table 1.A comparison with the previous Innsbruck cohort and between the Tel Aviv and Belgrade study cohorts is provided in Table S1 and S2.Validation of the 4-Item MSA-P Score In the newly recruited Tel Aviv-Belgrade cohort, 92% of the patients with a final MSA-P and 22% of those with a final PD diagnosis were classified at high-risk of suffering from MSA-P at early disease.The sensitivity of the 4-item MSA-P score for a final MSA-P diagnosis was 92% (95% confidence interval, c. i.:79-98%), the specificity 78% (95% c.i.:70-85%), the positive predictive value 57% (95% c.i.: 48-65%) and the negative predictive value 97% (95% c.i.:92-99%).The area under the ROC curve was 0.939 (95% c.i.:0.895-0.983).

Discussion
The 4-item MSA-P score was developed as a widely accessible tool to screen patients with early parkinsonism for their likelihood to suffer from MSA-a low MSA-risk was defined by scores of 0 to 1, while scores of 2-4 points indicated a high-risk.In the present validation cohort of patients from two independent centers, the sensitivity was higher compared to the original study (92% vs. 78%), while specificity was somewhat lower (78% vs. 86%), and the positive and negative predictive values for a final MSA-P diagnosis were similar (57% vs. 50% and 97% vs. 96%, respectively).The increased sensitivity is likely due to the fact that an OH diagnosis based on a standing test 17 and a history of urinary disturbances were sufficient to assign a point for the respective items of the MSA-P score in the present study.Such methodological decision was consciously taken bearing in mind that access to autonomic function testing 18 is often limited outside of MSA referral centers, 19 yet bedside screening measures like the standing test provide significant diagnostic and therapeutic guidance when included in the work-up of individuals with early parkinsonism.This same decision however also likely explains the lower specificity observed, since non-neurogenic causes of OH and urinary disturbances such as polypharmacy, perineal laxity in women or prostate hypertrophy in men were not systematically excluded like in the previous study.Despite such lower rigorousness in assessing autonomic disturbances, which is probably similar to that encountered in the diagnostic work-up of MSA in underserved geographical areas, the 4-item MSA-P score yielded an overall balanced accuracy for an early clinical distinction between MSA-P and PD.By including the pattern of dopaminergic responsiveness and development of postural deformities within 2 years from motor onset, the expanded 6-item MSA-P score gained specificity and positive predictive value compared to the original 4-item score.Even though one-third of MSA individuals may initially show some dopaminergic responsiveness, 1,20 this is in fact usually not as good as in PD and frequently associated with cranio-cervical or limb dystonia, in the absence of PD-typical limb dyskinesia. 21Postural deformities, such as antecollis and Pisa syndrome, also point against a PD diagnosis if developing early in the disease course. 8,22ur study has limitations.The present cohort lacked a neuropathological diagnosis and a quantitative assessment of dopaminergic responsiveness.The latter was due to the retrospective study design that also potentially introduced a selection bias and hindered a standardized documentation of autonomic disturbances eventually preceding motor symptoms.There was however a prolonged follow-up time of ≥24 months available, following which experienced neurologists carefully verified the neurological diagnosis against the latest PD and MSA diagnostic criteria. 7,8The latter were recently shown to have modest sensitivity, but consistently high specificity for a MSA diagnosis in neuropathological studies. 23,24ompared to the 2019 Innsbruck PD cohort 5 (n = 159), the newly recruited Tel Aviv-Belgrade PD cohort was significantly younger and on a lower number of medications per day, had a shorter disease duration at the time of head-up tilt or standing test and a longer follow-up time available (Table S1).
Compared to the 2019 Innsbruck MSA-P patients 5 (n = 27), the present MSA-P cohort showed comparable clinical-demographic characteristics, but had a longer follow-up time available (Table S1).
When comparing the participants between the Tel Aviv and Belgrade sites, both the PD and MSA-P study cohorts showed in-between sites clinical heterogeneities, but no significant differences in their distribution into low versus high risk of suffering from MSA-P according to the 4-items MSA-P score (Table S2).
a To inquire about stridor, physicians demonstrated it to the patients and their partners with their own voice, asking if they have ever heard such sound.We acknowledge that the partners of these two Tel Aviv PD cases might have misinterpreted nocturnal stridor with snoring.In recent years, science is moving towards a biological definition of a-synucleinopathies, 25 which is key for enrolling affected individuals in trials with technologies targeting the diseasespecific mechanisms of the disease.We are however still far for the implementation of biological diagnostic criteria in clinical practice and individuals with MSA are often diagnosed 4 to 5 years into their disease course. 26,27e conclude that a simple scoring system like the 6-item MSA-P score will aid selecting patients for studies of biomarker sensitivity and specificity, even in areas where autonomic function laboratories are not available.

TABLE 1
Clinical-demographic characteristics of the pooled Tel Aviv and Belgrade study population.

TABLE 1 Continued
Significant P values after Bonferroni correction for multiple comparisons are marked in bold.